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This information is intended for US healthcare professionals to access current scientific information about J&J Innovative Medicine products. It is prepared by Medical Information and is not intended for promotional purposes, nor to provide medical advice.

RISPERDAL® (risperidone)

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Adverse Event of RISPERDAL- Effect on Bone Mineral Density

Last Updated: 05/15/2024

Summary

As with other drugs that antagonize dopamine (D2) receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of PRL elevation than other antipsychotic agents.¹
Hyperprolactinemia may suppress hypothalamic gonadotropin-releasing hormone, resulting in reduced pituitary gonadotropin secretion. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.¹
There is conflicting clinical trial data regarding an association between risperidone-induced hyperprolactinemia and osteoporosis.²^-¹⁴

BACKGROUND

Osteoporosis is diagnosed by BMD measurement and occurrence of a fragility fracture (fracture occurring as a result of a fall from standing height or less with minimal or no trauma). BMD is important in predicting bone fracture risk. According to the National Osteoporosis Foundation, one standard deviation (SD) decrease in BMD in woman is equivalent to a 10-12% decrease in bone mass and a 1.5- to 2.6-fold increase in bone fracture risk. In order to determine peripheral bone density, a peripheral dual-energy x-ray absorptiometry (pDXA) scan can be performed on the forearm, heel, or finger. The gold standard for measuring BMD is a central dual-energy x-ray absorptiometry (DXA) scan that provides BMD measurements at the hip, spine, or femur; T-scores, and Z-scores. T-scores are used for diagnosis by comparing the patient’s BMD to the average BMD of a healthy 20- to 29-year-old, sex-matched, Caucasian reference population. A T-score of -1 to -2.5 indicates osteopenia and a score ≤-2.5 indicates osteoporosis. Z-scores compare the patient’s BMD to the mean healthy age- and sex-matched BMD. Z-scores ≤-2.0 may indicate a secondary cause for osteoporosis and is used for diagnosis in children, premenopausal women, and men <50 years old.¹⁵

Fracture risk can be determined through bone resorption (breakdown) and formation markers in the urine/serum. Examples of bone resorption markers include C-terminal crosslinking telopeptide of type 1 collagen (CTX) and N-terminal crosslinking telopeptide of type 1 collagen (NTX). Bone formation markers consist of osteocalcin, procollagen type 1 propeptides (P1NP), and bone-specific alkaline phosphatase. CTX and P1NP are among the most accurate serum marker tests for bone resorption and formation.¹⁵

CLINICAL STUDIES

Effects of Risperidone and Comparators on Bone Mineral Density

Study Design	Summary
Houghton et al (2021)¹⁶ performed a retrospective, propensity-score matched cohort study to evaluate and compare the risk of fracture among children with autism spectrum disorder (ASD) using RIS (n=3312) or ARI (n=3312). This study included children with ASD ages 2-18, who were new users or ARI or RIS and with no prior history of antipsychotic use of fractures. The primary outcome was any fracture during or within 90 days following study drug exposure. The mean length of study follow-up time, until fracture or censor, was 9.6 months for ARI and 10.0 months for RIS users.	In the ARI cohort, 101 (3.0%) patients had a fracture in follow-up versus 64 (1.9%) in the RIS cohort. Across the whole study period, this corresponded to a higher incidence rate (95% CI) of 38.4 (31.7–46.4) per 1000 patient-years for ARI versus 23.2 (18.2–29.6) per 1000 for RIS . The risk of any fracture was 40% lower among children with ASD who were using RIS versus ARI (HR and 95% CI: 0.60 [0.44–0.83]). The risk of fracture was visually comparable during the first 6-months of treatment but became greater in the ARI cohort near 1 year of exposure (log-rank p value over whole study period: 0.001).
Starki et al (2021)¹⁷ performed an experimental pre-test and post-test to compare the difference in serum calcium levels between men with schizophrenia treated with OLA (n=30) and RIS(n=30). Blood samples were taken from patients before receiving OLA and RIS treatment at the same hour, before activity, and before meals. The starting dose of OLA was 10 mg, titrated up to a maximum dose of 20 mg in response to the patient’s PANSS score. The starting dose of RIS was 4 mg, titrated up to a maximum dose of 8 mg in response to the patients PANNS score.	At week 0, the mean calcium level of patients was RIS 9.23± 0.48; OLA 9.12±0.50. At week 4, the mean serum calcium levels of patients were RIS 7.49 ± 0.54; OLA 7.8±0.51. There is a significant difference in serum calcium levels at week 0 and week 4 of RIS therapy (p < 0.001). There is a significant difference in calcium levels between patients in the OLA and the RIS treatment groups at week 4 (p=0.0023).
Chen et al (2021)¹⁸ performed a cross sectional study comparing the development of osteoporosis in patients taking RIS monotherapy (n=250) in comparison to healthy controls (n=288). For inclusion, patients in the RIS group must be undergoing RIS monotherapy for at least 6 months. Osteoporosis was defined as a decline in bone mineral density of the calcaneus. A 10 mL fasting blood sample was taken to measure serum levels of gonadal hormones (prolactin, estradiol, testosterone, progesterone, folic-stimulating hormone, luteinizing hormone).	The rates of osteoporosis were 24.4% (61/250) for patients on RIS therapy and 10.1% (29/288) for healthy controls. The patient group had a significantly higher rate of osteoporosis than the control group (P<0.001). Prolactin levels (OR = 1.1, 95% CI [1.08–1.15], P <0.001) and E2 levels (OR = 0.9, 95%CI [0.96–0.99], P=0.011) were significantly associated with osteoporosis in patients with schizophrenia.
Kuo et al (2020)¹⁹ performed a retrospective case-control study using Taiwan National Health Insurance Research Database to evaluate the relationship and risk of refracture in patients (N=7,842) diagnosed with schizophrenia taking antipsychotics. The effects of antipsychotics were evaluated according to their patterns of medication use. Continuous users were defined as patients receiving antipsychotic prescription both within 90 days and >90 days before the index date. Past users were defined as patients receiving antipsychotic > 90 days before index date, but not within 90 days. The purpose of this study is to evaluate the association between prolonged antipsychotic use and incidence of bone fractures and refractures.	Prolonged use of antipsychotics, regardless of types, was positively associated with increased risks of fractures. The highest risks of developing refractures were observed among patients with continuous use of three drugs: CLOR (OR= 2.45; 95% CI, 1.14−5.25), RIS (OR= 1.48; 95% CI, 1.01−2.16) and ZOT (OR= 2.15; 95% CI, 1.06−4.36)
Clapham (2020)²⁰ conducted a cohort study of 5 Swedish national registers to compare the risk of osteoporosis-related fractures in adult patients exposed to RIS and other atypical or typical antipsychotics. Registers were used to ID adults with 2 consecutive new dispensations of RIS (n=38,211), other atypical antipsychotics excluding paliperidone (n=60,691), and typical antipsychotics (n=17,445) within 3 months between 2006 and 2013. Patients who had active cancer or a pituitary tumor, taken paliperidone anytime prior to start of follow up, non-open hip fractures related to osteoporosis prior to exposure to index rate or within 6 months after exposure to index rate and patients who switched from one antipsychotic to another or were treated with more than one antipsychotic drug were excluded. An osteoporosis-related fracture was defined as a non-open hip/femur fracture which was the primary outcome. The secondary outcome was non-hip/femur fractures.	The mean ages for RIS, other atypical and typical antipsychotics were 68, 44, and 63 years, respectively. There was no significant difference between RIS and other atypical antipsychotics for the risk of fracture (adjusted HR: 1.04, 95% CI: 0.91-1.19). Age stratified analysis also did not show a significant difference in the risk of fractures. For treatment naïve patients, there was no significant difference in the risk of non-open hip/femur fractures between RIS and other atypical antipsychotics (adjusted HR: 1.04; 95% CI: 0.90–1.21). There was a significant increase risk of non-open hip/femur fractures for typical antipsychotics compared with other atypical antipsychotics in the overall study and treatment-naïve patient population. After age stratification, the risk increase remained statistically significant for the 45-65 and >65 years of age groups. For non-hip/femur fractures, there were no statistically significant differences between RIS and other atypical antipsychotics or other atypical and typical antipsychotics in the overall study population.
Shen (2019)²¹ conducted a retrospective cohort study using data from the Taiwan National Healthcare Insurance database to evaluate the risk of hip/femur fracture in adult patients treated with RIS (n=73,315) compared to other atypical (n=120,538) and typical antipsychotics (n=147,095). A nested case-control group evaluated the association between hip/femur fracture and current, recent and past exposure to RIS compared with other atypical antipsychotics. Cases were patients with newly diagnosed osteoporotic fracture. The primary study outcome was an inpatient hip/femur fracture who had hip/femur surgical procedures and/or x-ray within 4 weeks of fracture diagnosis.	Across the 3 groups, the mean age ranged from 50.3 to 54.8 years of age. Mean duration of follow-up was 1.56 years for the RIS group, 1.29 years for the other atypical antipsychotic group and 0.95 years in the typical antipsychotic group. The adjusted HR of hip/femur fracture was 0.92 (CI 0.84-1.01) and 0.996 (CI 0.89-1.11) for other atypical and typical antipsychotics compared to RIS, respectively. The adjusted HR in other atypical antipsychotics compared to RIS in patients ≥80 years old was 0.93 (95%CI 0.8-1.08). There was no significant difference in the risk of non-hip/femur fractures in either the other atypical or typical groups compared with RIS In the case control group, there was no difference in the risk of osteoporosis-related hip/femur or non-hip/femur fractures in patients exposed to other atypical antipsychotics compared with RIS. The adjusted odds ratio for hip/femur fractures was 0.92 (CI 0.83-1.01) in patients exposed to atypicals vs RIS for 1 year prior to fracture date, 0.97 (CI 0.87-1.07) during 1-3 years prior, and 0.92 (CI 0.81-1.06) 3-5 years prior to fracture date.
Calarge (2018)²² conducted a 36-week placebo controlled, DB prospective study of RIS treated male children and adolescents (aged 5-17 years) supplemented with calcium and vitamin D to examine bone mineralization promotion in RIS induced hyperprolactinemia (total N =47; mean age: 11.0±2.6 years) Patients had no supplementation of calcium or vitamin D 3 months prior to study start, a minimum of 1-year RIS treatment and a diagnosis of hyperprolactinemia (prolactin level ≥18.4 ng/mL). Patients received daily doses of 1250 mg calcium carbonate and 400 IU of vitamin D₃(n=23) or placebo (n=24).	Of the total patients completing the study (N= 47), from baseline to week 36, and after intervention, the TBLH BMD Z-score was not significant (β=0.0062 ± 0.0807, P>0.90). After adjusting for age, physical activity, and forearm length, the effect on trabecular BMD was not significant (β=-4.8 ± 5. 6, P>0.30). Change in bone strength index, cortical BMD, cortical thickness, periosteal and endosteal circumference, and polar section modulus after intervention were also not significant.
Calarge et al (2017)²³ compiled data from four independent studies to examine skeletal health in children and adolescents with ASD in comparison to patients with other psychiatric disorders. Three studies included patients who had been taking RIS for at least 6 or 12 months and the fourth included patients who had initiated RIS treatment within the prior month. Volumetric BMD was estimated using DEXA and pQCT at the nondominant radius.	A total of 186 boys age 5-17 years with (n=30) or without (n=156) ASD were analyzed in this study. There was a significant difference between groups in the amount of physical activity (1.6±1.2 vs 2.6±1.1, respectively, P=0.0001) as well as multivitamin use (40% vs 15%, respectively, P=0.0013). After adjusting for age, height, BMI, and SSRI use, having a diagnosis of ASD was associated with a significantly lower volumetric BMD at the radius (P=0.004). Adjusting for physical activity, dietary calcium and vitamin D intake, and duration of RIS treatment did not substantially alter results (P<0.02). Additionally, diagnosis with ASD was associated with a lower bone strength index (P<0.009). Again, adjusting for physical activity, dietary calcium and vitamin D intake, and duration of RIS treatment did not substantially alter the results (P<0.04).
Torstensson (2017)²⁴ is a nationwide register-based cohort study exploring the association between fragility fractures and antipsychotics. The study population included Denmark residents 65 or older who had no antipsychotic use 1 year prior to the study (N=1,540,915). Of this population, patients received one of the following antipsychotics: RIS (n=23,970), olanzapine (n=15,250), quetiapine (n=13,677), zuclopenthixol (n=11,622), chlorprothixene (10,089), flupentixol (11,234), levomepromazine (14,857), or haloperidol (17,396).	Patients were followed for approximately 9.6 years with fragility fractures occurring in 16% of patients; 2.9% while on APs. APs were associated with increased IRRs of fractures compared to unexposed. Associations were highest during the first 30 days of treatment with APs (overall adjusted IRR 2.23). Adjusted IRRs for RIS were: 1.97 (0-30 days), 1.3 (31-365 days), 1.09 (>365 days). There were no significant differences between IRRs of the SGAs.
Calarge et al (2015)² conducted a longitudinal study of male children and adolescents (aged 7-17 years; mean age: 11.8 years at study entry) treated with RIS for ≥6 months to examine skeletal effects of SSRI treatment and continuing vs discontinuing RIS between study entry and follow-up, 18 months after study entry (N=94). At study entry, patients received RIS and SSRIs for a mean ±SD of 2.5±1.7 years and 1.6±1.9 years, respectively.	At follow-up, 70 patients had continued RIS and 24 patients had discontinued RIS. A total of 37 patients did not receive SSRIs at study entry or follow-up and 44 patients received SSRIs at study entry and follow-up. Continuing RIS was associated with a decline in a participant’s age-sex-height-race–specific areal BMD Z-score at the lumbar spine (P<0.04) and failure to increase radius trabecular volumetric BMD (P<0.03), after accounting for significant covariates, between study entry and follow-up. SSRIs were associated with reduced lumbar spine areal BMD Z-score and radius trabecular volumetric BMD at both study entry (P<0.02 and P<0.03, respectively) and follow-up (P<0.06 and P<0.03, respectively). However, the differences were not significant between both time periods.
Lin et al (2015)³ conducted a systematic, multi-center study to examine sex-specific risk factors of low BMD in Taiwanese patients with schizophrenia (N=195; 80 men and 115 women). -Patients in the study received, either alone or in combination: OLA, QUE, ARI, CLO, typical antipsychotics, RIS, amisulpride, PAL, and ZIP (breakdown of specific treatments not specified).	In men, hyperprolactinemia (B=-0.821, P=0.009), body weight (B=0.024, P=0.046), and GAF score (B=0.027, P=0.043) were associated with the DEXA T-score (adjusted R²=0.254). In women, postmenopausal (B=-1.070, P<0.001), body weight (B=0.027, P=0.003), and PANSS positive-subscale score (B=0.094, P<0.001) were associated with the DEXA T-score (adjusted R²=0.282).
Wang et al (2014)⁴ conducted a 12-month prospective study. Participant’s blood samples and BMD were taken at baseline and 12 months later to evaluate the effects of antipsychotics on BMD and prolactin levels in patients with schizophrenia.	Post-treatment BMD values in patients (ranging from 1.02±0.15 to 1.23±0.10) were significantly lower than that in healthy controls (ranging from 1.15±0.12 to 1.42±1.36). The BMD values after conventional antipsychotics were significantly lower than that after atypical antipsychotics. The prolactin level after conventional antipsychotics (53.05±30.25 ng/ml) was significantly higher than that after atypical antipsychotics (32.81±17.42 ng/ml).
Takahashi et al (2013)⁵ conducted a longitudinal, prospective, observational study evaluating the effect of prolactin-raising antipsychotics (n=141; mean age: 58.3 years) vs prolactin-sparing antipsychotics (n=23; mean age: 59.9 years) on BMD for up to 5 years in Japanese schizophrenic patients. Prolactin-raising antipsychotics included: first-generation antipsychotics, RIS, and blonaserine. Prolactin-sparing antipsychotics included: ARI, OLA, QUE, and perospirone.	There was no significant difference in mean BMD Z-score between the 2 groups at baseline (P=0.42). During a mean follow-up period of 3.4±1.6 years, there was a difference in the time course of BMD Z-scores between the 2 groups (P=0.011). The z-scores of the prolactin-raising group did not change over time; whereas, the scores of the prolactin-sparing group increased over time. However, no significant difference was found in BMD Z-score at each time point (12, 24, 36, 48, and 60 months) between the 2 groups.
Bishop et al (2012)⁶ conducted an open-label study assessing the effects of prolactin elevation on serum markers of bone formation (e.g., osteocalcin) and resorption (e.g., NTx) during the first 4 weeks of RIS treatment (median dose: 3 mg/day; range: 0.5-6 mg/day) in 30 patients (mean age: 24 years; 63% male) who were antipsychotic free at baseline and diagnosed with psychosis.	From baseline to week 4, mean serum prolactin levels significantly increased from 12.1 (±1.9) ng/mL to 65.7 (±12.2) ng/mL, respectively (adjusted for gender, age, BMI and RIS dose; P<0.001). In addition, mean NTx values significantly decreased from 18.31 (±1.49) nM BCE to 15.5 nM BCE after 4 weeks of treatment (adjusted for gender, age, BMI and RIS dose; P<0.05), while osteocalcin, NTx: osteocalcin ratios, estradiol, and testosterone did not significantly change. A correlation between the magnitude of change in prolactin to the change in NTx after treatment trended towards significance (r=0.33; P=0.07; small sample size limitations noted in study). No significant correlations between RIS dose and prolactin were observed (r=0.06; P=0.77).
Lee et al (2010)⁷ conducted a cross-sectional study examining the effect of hyperprolactinemia and negative symptoms of schizophrenia on BMD in 45 male schizophrenic patients (mean age: 49.5 years) receiving RIS (n=20), OLA (n=15), or CLO (n=10) for ≥1 year. Exclusion criteria included: History alcohol/substance abuse; history of bone fracture within 1 year; diseases/symptoms impairing physical mobility (EPS; Parkinson's); concomitant Axis I disease; concomitant use of mood stabilizers, antidepressants, or anxiolytics; serious internal disease that may affect BMI Mean Chlorpromazine Equivalents: RIS (252.5 mg/day), OLA (273.7 mg/day), CLO (265 mg/day) Endpoints: DEXA scan utilized to measure BMD T-score and Z-score (L1-L4, femoral neck, trochanteric, and intertrochanteric regions of left hip), 8 AM blood samples utilized to measure hormones affecting bone metabolism (estradiol, progesterone, testosterone, FSH, LH, thyroid hormones, prolactin, cortisol) and bone markers (plasma bone alkaline phosphatase, osteocalcin, ICTP, urinary calcium and phosphorus), PANSS	Baseline demographics, BMD Z-scores, and laboratory results were similar between treatment groups, with the exception of prolactin levels, which were significantly higher in the RIS vs CLO group (33.3 ng/mL vs 10.5 ng/mL, respectively). Number of patients with hyperprolactinemia, osteoporosis, or osteopenia per treatment group: RIS (n=20): 15, 3, and 3, respectively OLA (n=15): 6, 0, and 7, respectively CLO (n=10): 1, 0, and 1, respectively In the 22 patients with hyperprolactinemia, no correlation was observed between hyperprolactinemia and BMD. Multivariate analysis showed that BMD was significantly affected by the subscale of negative symptoms.
Abbreviations: AM, morning; ARI, aripiprazole; ASD, Autism Spectrum Disorders; BCE, bone collagen equivalent; BMD, bone mineral density; BMI, body mass index; CLO, clozapine; CLOR, chlorpromazine; DEXA, dual-energy x-ray absorptiometry; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition; EPS, extrapyramidal symptoms; FLU, fluphenazine; FSH, follicle stimulating hormone; GAF, Global Assessment of Functioning; HAL, haloperidol; ICTP, C-terminal telopeptide type I collagen; IRR, incidence rate ratio; L, lumbar; LH, luteinizing hormone; NTx, n-telopeptide crosslinks; OLA, olanzapine; PAL, paliperidone; PANSS, Positive and Negative Syndrome Scale; pQCT, peripheral quantitative computed tomography; QUE, quetiapine; RIS, risperidone; SD, standard deviation; SSRI, selective serotonin reuptake inhibitor; ZIP, ziprasidone; ZOT, zopetine.

Other Relevant Literature

Additional studies have been referenced.⁸^-¹⁴^,²⁵

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 08 April 2024.

References

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1	RISPERDAL (risperidone) [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/RISPERDAL-pi.pdf.
2	Calarge CA, Burns TL, Schlechte JA, et al. Longitudinal examination of the skeletal effects of selective serotonin reuptake inhibitors and risperidone in boys. J Clin Psychiatry. 2015;76(5):607-613.
3	Lin CH, Lin CY, Huang TL, et al. Sex-specific factors for bone density in patients with schizophrenia. Int Clin Psychopharmacol. 2015;30(2):96-102.
4	Wang M, Hou R, Jian J, et al. Effects of antipsychotics on bone mineral density and prolactin levels in patients with schizophrenia: a 12‐month prospective study. Hum Psychopharmacol. 2014;29(2):183-189.
5	Takahashi T, Uchida H, John M, et al. The impact of prolactin-raising antipsychotics on bone mineral density in patients with schizophrenia: findings from a longitudinal observational cohort. Schizophr Res. 2013;147(2-3):383-386.
6	Bishop JR, Rubin LH, Reilly JL, et al. Risperidone-associated prolactin elevation and markers of bone turnover during acute treatment. Ther Adv Psychopharmacol. 2012;2(3):95-102.
7	Lee TY, Chung MY, Chung HK, et al. Bone density in chronic schizophrenia with long-term antipsychotic treatment: preliminary study. Psychiatry Investig. 2010;7(4):278-284.
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11	Becker D, Liver O, Mester R, et al. Risperidone, but not olanzapine, decreases bone mineral density in female premenopausal schizophrenia patients. J Clin Psychiatry. 2003;64(7):761-766.
12	Abraham G, Paing WW, Kaminski J, et al. Effects of elevated serum prolactin on bone mineral density and bone metabolism in female patients with schizophrenia: a prospective study. Am J Psychiatry. 2003;160(9):1618-1620.
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16	Houghton R, van den Bergh J, Law K, et al. Risperidone versus aripiprazole fracture risk in children and adolescents with autism spectrum disorders. Autism Res. 2021;14(8):1800-1814.
17	Starki S, Loebis B, Husada SM, et al. Calcium levels differences in men with schizophrenia treated with olanzapine and risperidone in Prof. Dr. M Ildrem Psychiatric Hospital, Medan. Open Access Maced J Med Sci. 2021;9(T3):274-279.
18	Chen Y, Zhang Y, Fan K, et al. Association between gonadal hormones and osteoporosis in schizophrenia patients undergoing risperidone monotherapy: a cross-sectional study. PeerJ. 2021;9:e11332.
19	Kuo CM, Liao WJ, Huang CC, et al. Antipsychotic medication in schizophrenic patients is associated with higher risks of developing bone fractures and refractures. Clin Psychopharmacol Neurosci. 2020;18(4):562-570.
20	Clapham E, Bodén R, Reutfors J, et al. Exposure to risperidone versus other antipsychotics and risk of osteoporosis‐related fractures: a population‐based study. Acta Psychiatr Scand. 2020;141(1):74-83.
21	Shen SP, Liu Y, Qiu H, et al. The risk of bone fracture after long-term risperidone exposure is not increased compared to other atypical antipsychotics: a retrospective cohort study. PLoS One. 2019;14(9):e0221948.
22	Calarge CA, Mills JA, Ziegler EE, et al. Calcium and vitamin D supplementation in boys with risperidone-induced hyperprolactinemia: a randomized, placebo-controlled pilot study. J Child Adolesc Psychopharmacol. 2018;28(2):145-150.
23	Calarge CA, Schlechte JA. Bone mass in boys with autism spectrum disorder. J Autism Dev Disord. 2017;47(6):1749-1755.
24	Torstensson M, Leth-Møller K, Andersson C, et al. Danish register-based study on the association between specific antipsychotic drugs and fractures in elderly individuals. Age Ageing. 2017;46(2):258-264.
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